Abstract
The casitas b-lineage lymphoma (c-Cbl) is an important adaptor protein with an intrinsic E3 ubiquitin ligase activity that interacts with E2 proteins such as UbCH7. c-Cbl plays a vital role in regulating receptor tyrosine kinase signaling. c-Cbl involves in whole-body energy homeostasis, which makes it a potential target for the treatment of type 2 diabetes and obesity. In the present study, we have designed two parental peptides and 55 modified peptides based on the structure of UbCH7 loop L1 and L2. Thirteen of the modified peptides showed increased inhibitory activity in a fluorescence polarization-based assay. In the in vivo proof of study principle, mice treated with peptides 10, 34, 49 and 51 were protected against high-fat diet-induced obesity and insulin resistant. These inhibitors may potentially lead to new therapeutic alternatives for obesity and type 2 diabetes.
Highlights
The incidence of obesity and type 2 diabetes is increasing throughout the world and currently affects about 250 million people worldwide
It has been recently reported that c-Cbl-/- mice exhibited a lean phenotype and enhanced peripheral insulin actions likely due to elevated energy expenditure [3]
Peptides derived from UbCH7 L1 and L2 loop inhibit c-Cbl and the probe binding in Fluorescence polarization (FP) assay in vitro
Summary
The incidence of obesity and type 2 diabetes is increasing throughout the world and currently affects about 250 million people worldwide. Possible causes of this health problem are credited partially to several risk factors. Researchers described a number of genes that regulate food absorption, appetite, and increased energy expenditure in either adipose or muscle tissue over the past decade [1, 2]. The Casitas B-lineage Lymphoma protein c-Cbl is one of these genes, and it is known to regulate whole-body energy expenditure [3]. It has been recently reported that c-Cbl-/- mice exhibited a lean phenotype and enhanced peripheral insulin actions likely due to elevated energy expenditure [3]. The function of the c-Cbl protein, which is responsible for the lean phenotype, remains unclear because Cbl proteins involve in both the PLOS ONE | DOI:10.1371/journal.pone.0135916 August 21, 2015
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